3.2. TFIIH and XP/CS Symptoms
Cockayne Syndrome (CS) is also an autosomal recessive disorder, characterized by neurodegeneration and premature aging. Other CS phenotypes include cerebellar atrophy and demyelination. There are multiple proteins within the NER pathway that lead to CS, particularly for the two initiation factors in TC-NER, CSB and CSA. Several mutations in CSB or CSA have been shown to cause CS, but they do not lead to XP, suggesting CS is specifically related to defective TC-NER activity (Fousteri & Mullenders, 2008; Rapin et al., 2000). The mechanism of CS is especially interesting and puzzling, because UV damage does not directly occur in the brain and it is unknown to what extent failure to repair bulky lesions in active genes in neuronal cells contributes to the onset of CS. Alternatively, previous studies suggest that CS may be caused by defective repair of oxidative damage and/or improper expression of genes related to neuron development (Y. Wang et al., 2014). Interestingly, a small number of mutations in the XPD gene are associated with XP combined with CS (XP/CS) (Lehmann, 2001; Rapin et al., 2000). If TC-NER deficiency plays a causative role in CS, these XP/CS mutations in XPD may cause deficiency in both subpathways in NER. The identified XP/CS mutations are located either within the conserved helicase motif, or in the p44-interacting domain (Lehmann, 2001). Why these mutations cause both XP and CS symptoms whereas the majority of other XPD mutations lead to XP disease, but no CS, remains unclear.